| The First Part The Role of the Renal Renin-angiotensin System in the Pathogenesis of Childhood Immune NephropathyObjective To determine the changes in angiotensin II(Ang II),angiotensin-converting enzyme 1(ACE1),angiotensin-(1-7)[Ang-(1-7)],angiotensin-converting enzyme 2(ACE2)in renal tissues and urinary angiotensinogen(uAGT)content of children with immune nephropathy,and to evaluate the correlation between local activation of the renin-angiotensin system(RAS)and severity of the renal disease,and the potential of uAGT as a biomarker of renal RAS activation.Methods 21 cases of primary nephrotic syndrome(PNS),30 cases of IgA nephropathy(IgAN),5 cases of acute poststreptococcal glomerulonephritis(APSGN),1 case of C3 glomerulonephritis(C3GN),103 cases of Henoch-Schonlein purpura nephritis(HSPN),11 cases of lupus nephritis(LN),and 1 case of hepatolenticular degeneration(HLD)with renal injury,all pathologically confirmed by renal biopsy,were included for cross-sectional study.General condition and clinical indexes of the children were recorded,expression levels of Ang ?,ACE1,Ang-(1-7)and ACE2 in children's kidneys were determined by immunohistochemistry,uAGT of these children were determined by ELISA.Immunohistochemistry results were analyzed by a computerized image processing system.And the correlation between uAGT content and components of RAS as well as 24h urinary protein excretion was analyzed.Kidney biopsy results of 44 cases of mild glomerular lesions(the control group)were used as control for assessment of the renal indexes,and control for serum and urinary indexes were obtained from both the control group and another 50 children that had a health examination in our hospital from June 2018 to December 2018(the healthy group)Results(1)Children with PNS showed higher renal Ang ?,ACE1 expression,and lower ACE2,Ang-(1-7)expression compared to the control group(P<0.05);higher uAGT/uCr compared to the control and healthy group(P<0.05);and uAGT/uCr level was correlated with expression of components of RAS and 24h urinary protein excretion(P<0.05)(2)Children with IgAN showed higher renal Ang ?,ACE1 expression,and lower ACE2,Ang-(1-7)expression compared to the control group(P<0.05),and the difference was more evident in cases with more severe pathological grade;these patients also had higher uAGT/uCr compared to the control and healthy group(P<0.05);and uAGT/uCr level was correlated with expression of components of RAS and 24h urinary protein excretion(P<0.05)(3)Children with HSPN showed higher renal Ang ?,ACE1 expression,and lower ACE2,Ang-(1-7)expression compared to the control group(P<0.05),and the difference was more evident in cases with more severe pathological grade;these patients also had higher uAGT/uCr compared to the control and healthy group(P<0.05);and uAGT/uCr level was correlated with expression of components of RAS and 24h urinary protein excretion(P<0.05)(4)Children with LN showed higher renal Ang ?,ACE1 expression,and lower ACE2,Ang-(1-7)expression compared to the control group(P<0.05),and the difference was the most evident in children with grade ? cases;these patients also had higher uAGT/uCr compared to the control and healthy group(P<0.05);and uAGT/uCr level was correlated with expression of components of RAS and 24h urinary protein excretion(P<0.05)(5)Children with APSGN,C3GN,HLD with renal injury also showed higher renal Ang?,ACE1 expression,and lower ACE2,Ang-(1-7)expression compared to the control group and uAGT/uCr levels of these children were higher than those of the control and healthy groupsConclusion Local RAS activation is seen in most cases of immune nephropathy in children,and RAS activity is positively correlated severity of disease.uAGT/uCr can be used as a biomarker for RAS activation in kidney,and has great clinical significance in assessment of severity of kidney diseaseThe Second Part Angiotensin(1-7)Attenuates Sepsis-associated Acute Kidney Injury via Regulating the NF-?B Signal PathwayObjective To observe the occurrence of lipolypolysaccharide(LPS)-induced acute kidney injury(SA-AKI)in mice and the effect of angiotensin(1-7)[Ang-(1-7)]on renal histomology,renal renin-angiotensin system(RAS),inflammatory response,oxidative stress and NF-?B signaling pathway in SA-AKI mice.To explore the relationship between renal RAS activation and NF-?B signaling pathway activation in SA-AKI mice and the molecular mechanism of Ang-(1-7)protective effect on SA-AKI miceMethods The experimental model for SA-AKI mice was established by intracervical injection of LPS,and Ang-(1-7)was administered.80 male C57BL/6 inbred mice were divided into 4 groups(20 in each group)according to the random number table:normal control group,Ang-(1-7)group,sepsis group(LPS group),sepsis plus Ang-(1-7)group [LPS+Ang-(1-7)group].The levels of urea nitrogen and creatinine in serum were determined by automatic biochemical analyzer,and the changes of inflammatory index were detected by ELISA.The change of oxidative stress index in renal cortex was detected by chemical colorimetry.The expression of Ang ? in renal tissue was examined by immunohistochemical technique.Western Blot was used to detect the expression of NF-?B-p65 and I?B? in renal tissue.And the pathological changes of renal tissue were observed in each group.Results(1)Compared to the normal control group,the levels of serum creatinine and urea nitrogen were increased(P<0.05)in SA-AKI mice;the levels of TNF-?,IL-1?,IL-6,MDA levels were significantly increased;the expression of Ang ? and phosphorylation of NF-?B were also elevated in renal tissue;the SOD,T-AOC levels and IKBa expression in renal tissue was sharply decreased(P<0.05);the pathological kidney injury was evident.(2)After Pearson correlation analysis,it showed a positive correlation between renal Ang ? and relative protein content of NF-?B-P65,and a negative correlation between renal Ang ? and relative protein content of I?B?(P<0.05).(3)The levels of urea nitrogen,creatinine,TNF-?,IL-1?,IL-6,MDA and the expression of Ang ? and phosphorylation of NF-?B in renal tissue in Ang-(1-7)administered group were lower than those in SA-AKI group,while the levels of SOD,T-AOC and IKBa expression were higher than those in SA-AKI group(P<0.05);the pathological changes showed diminished kidney damage.Conclusion(1)The LPS-induced SA-AKI to mice leads to over activation of rennal RAS,an increase in Ang ?,severe inflammatory injury and oxidative stress,activation of NF-?B in renal inflammatory pathway.(2)Rennal RAS activity of SA-AKI mice was correlated with the activation degree of NF-?B.(3)Ang-(1-7)can decrease the level of Ang ?,down-regulate the expression of NF-?B pathway,reduce inflammatory response and oxidative stress,and mitigate SA-AKIConclusion The LPS-induced AKI to mice leads to over activation of RAS,an increase in renal Ang ?,severe inflammatory injury and oxidative stress,activation of NF-?B in renal inflammatory pathway.Ang-(1-7)can decrease the level of renal Ang ?,down-regulate the expression of NF-?B pathway,reduce inflammatory response and oxidative stress,and mitigate sepsis-associated AKI. |
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